Fig. 3.

Claudin 18.1 (CLDN18.1) is a tumor suppressor in alveolar epithelial cells. In normal alveolar epithelial cells, CLDN18.1 binds to Zonula Occludens-1 (ZO-1) and Hippo kinases (p-LATS) in normal alveolar epithelial cells to form a complex. Yes-associated protein (YAP) is phosphorylated by p-LAST and anchored at this complex, inhibiting YAP translocation to the nucleus. Meanwhile, inhibition of YAP can preserve the activity of phosphatase and tensin homolog (PTEN), thereby inhibiting phosphatidylinositol 3-kinase/phosphoinositide-dependent kinase 1 (PI3K/PDK1)/AKT signaling pathway. CLDN18.1 can also directly inhibit PDK1, AKT, and insulin-like growth factor-1 receptor (IGF-1R). In lung cancer cells, deletion of Cldn18.1 causes YAP activation and translocation to the nucleus to promote cancer cell proliferation. Meanwhile, activated YAP can inhibit the activity of PTEN and activate the PI3K/PDK1/AKT signaling pathway, which further promotes cancer cell proliferation.